infections Susanne Matthes-Martin, Tobias Feuchtinger, Peter Shaw, - - PowerPoint PPT Presentation

Management of adenovirus (ADV) infections

Susanne Matthes-Martin, Tobias Feuchtinger, Peter Shaw, Dan Engelhard, Per Ljungman

ADV: Definitions I

• Primary infection:

First infection in infancy and childhood

• Reactivation:

Endogenous reactivation in immunocompromized patients

• Reinfection:

Infection with a new subtype.

• Systemic infection / viremia: Positive PCR, virus isolation or Ag

detection in blood

• Local infection:

Positive PCR, virus isolation or Ag detection in body fluids.

ADV: Definitions II

• Probable disease

Infection plus symptoms and signs without histological confirmation

• Proven disease:

Infection plus symptoms related to the infection and histological confirmation

• fever
• enteritis
• hepathopathy
• nephritis
• Detection of ADV in stool + enteritis
• Detection of ADV in urine + nephritis
• Detection of ADV in PB +

together with negative diagnostic tests indicative for bacterial

• r fungal infection
• Detection of ADV in organ biopsy
• Detection of ADV in cerebrospinal fluid
• Multiple organ failure, high viral load in PB and detection of

ADV in autoppsy

ADV Infection: high risk patients

Children:

• allo-SCT with in-vivo or ex-vivo T-cell depletion
• allo-SCT with unrelated donor graft
• allo-SCT with unrelated cord blood graft
• severe (Gr III-IV) Graft versus Host Disease
• severe lymphopenia (< 300 CD3+ cells/µl PB)

Adults:

• post allo-SCT haploidentical donor or unrelated

cord blood graft

• severe (Gr III-IV) Graft versus Host Disease
• treatment with Alemtuzumab

ADV Infection in the immunocompromized host: sings and symptoms

• Fever
• Enteritis
• Hepathopathy
• Nephritis
• Retinitis
• Encephalitis

Recommendation ADV: diagnostic techniques

• PCR is fast and has higher sensitivity and specificity

compared to culture or IF (AII)

• Quantitative PCR is more predictive for lethal disease

(AII)

• Quantification in stool samples helps to identify patients

(primarily children) at risk for viremia (BIII)

• Subtyping of adenovirus might yield additional information
• Quantitative PCR - either commercial or in-house

(validated by round-robin tests) is the current gold standard and should be used (A II)

ADV: diagnostic studies

• High incidence of ADV-infection post allo-SCT in children
• Low incidence of ADV-infection post allo-SCT in adults.
• Incidence increases with degree of immunosuppression both in adults

and children

• High mortality in case of ADV-viremia
• ADV infection is a rare event following autologous SCT
• No screening studies available for children with chemotherapy
• Single cases of lethal ADV hepatitis in children with ALL

Recommendation ADV-screening in allo SCT (children):

• Quantitative PCR-screening on PB is recommended on an at least

weekly basis to patients at risk (AII)

• Screening is not routinely recommended in patients receiving

matched sibling grafts (BII)

• Length of screening should be adapted according to degree
• f immune reconstitution (BIII)

Recommendation ADV-screening in allo SCT (adults):

• Routine screening is not routinely recommended in standard risk

patients (BII)

• For high risk patients screening should be considered (BIII)
• Length of screening should be adapted according to degree
• f immune reconstitution (CIII)

Recommendation ADV-screening in auto SCT and chemotherapy:

• no viral screening warranted (BII)
• quantitative PCR in case of clinical suspicion (BIII)

Recommendation ADV-monitoring in case of viremia:

• In patients with ADV-viremia viral load should be monitored by

quantitative PCR at least once weekly (AII)

ADV: Prophylactic virostatic treatment

Bruno et al 2003 lower incidence of ADV infection in patients receiving prophylactic ganciclovir Avivi et al 2004 trend towards lower incidence No data on cidofovir or ribavirin Ganciclovir:

Recommendation prophylactic treatment: Prophylactic antiviral therapy is not recommended (BIII)

ADV recommendation for preemptive treatment of asymptomatic viremia:

Goal: To prevent ADV disesase Indication to start preemptive treatment:

ADV viremia plus presence of at least one risk factor Children:

• allo-SCT with in-vivo or ex-vivo T-cell depletion
• allo-SCT with unrelated donor graft
• allo-SCT with unrelated cord blood graft
• severe (> Gr II) Graft versus Host Disease
• severe lymphopenia (< 300 CD3+ cells/µl PB)

Adults:

• post allo-SCT haploidentical donor or unrelated cord blood graft
• Gr III-IV acute Graft versus Host Disease
• following treatment with Alemtuzumab

(BIII) (BII) Viral loads should be monitored during therapy (BIII)

ADV recommendation for treatment indication:

Indication to start treatment:

• Proven ADV disease
• Probable ADV disease

(BIII)

Adenovirus – treatment options

• Antiviral drugs
• Cidofovir
• Ribavirin
• Ganciclovir
• CMX001 (oral lipid derivate of cidofovir; non-licensed)
• Other options
• Iv Ig
• Transfer of adenovirus specific T-cells (experimental)
• Reduction/withdrawal of immunosuppression

• Iv. cidofovir is recommended as first line therapy (BIII)
• Studies of preemptively given cidofovir suggests efficacy in reducing viral

load

• No clear data to support that preemptive cidofovir reduces the incidence of

ADV disease

• No clear data regarding efficacy in treating adenovirus disease
• Varying doses and schedules have been used most commonly 5 mg/kg

weekly (2-3 doses) thereafter every other week. There is no evidence supporting one particular schedule

• Supportive measures should be taken with oral probenecid

hyperhydration, and if possible avoidance of other nephrotoxic drugs at day of cidofovir administration (BIII)

ADV recommendation for treatment I:

• Ribavirin is not generally recommended for adenovirus

infection but can be considered in cases with type C infections especially in patients with decreased renal function (CIII)

• Consider the addition of iv Ig (BIII)
• Immunosupression should be reduced whenever

possible (AII)

• For systemic adenovirus disease, virus specific CTLs

can be considered if available (B III)

ADV recommendation for treatment II:

Future developments

• Lower risk for ADV-associated disease and ADV-associated

mortality has been shown in the presence of ADV-specific T-cells

• Safety and feasibility of adenospecific T-cell transfer has been shown

(Feuchtinger et al BJH 2006; Leen et al, Nature Medicine 2006)

• Adenospecific T-cell transfer is a promising strategy but there are still

limited data on efficacy and further studies are neded (Leen et al Blood 2009; Feuchtinger et al. 2009)

• Multispecific CTLs are in development
• CMX001, a cidofovir lipid conjugate, has shown efficacy in

a phase II study